Mitochondrial DNA (mtDNA) depletion syndrome (MDS) encompasses a group of genetic disorders characterized by a severe reduction in mtDNA content leading to respiratory chain deficiency in affected tissues and organs. MDS arises due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis, deoxyribonucleoside triphosphate (dNTP) metabolism or mtDNA replication. There are also some MDSs with unknown pathophysiology.
Some exemplary MDSs are deoxyguanosine kinase (DGUOK) deficiency, thymidine kinase 2 (TK2) deficiency, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), mitochondrial DNA polymerase (POLG) deficiencies (including Alpers-Huttenlocher syndrome, SANDO syndrome, MIRAS, etc.), MPV17-related hepatocerebral and RRM2B-related myopathies. Of known mutations, there are over ten genes that have been linked to MDS (TK2, DGUOK, POLG, MPV17, RRM2B, SUCLA2, SUCLG1, TYMP, C10orf2, and SAMHD1).
Direct supplementation with nucleosides, deoxyribonucleoside monophosphates (dNMPs), deoxyribonucleoside diphosphates (dNDPs) or dNTPs has shown the ability to rescue mtDNA depletion in in vitro models of MDS and increase overall survival in animal models of MDS in vivo. However, the pharmacological prospects for nucleosides, dNMPs, dNDPs and dNTPs as practical treatments for MDS in humans are low. The negatively charged phosphates on dNMPs, dNDPs and dNTPs preclude diffusion across cellular membranes. Furthermore, intra- and extracellular phosphatases effectively dephosphorylate dNMPs, dNDPs and dNTPs to the base nucleoside prior to reaching the desired site of action. Although the base nucleoside can enter the cell via passive and active transport mechanisms, it cannot by itself address the deficiencies of MDS given that phosphorylation of a nucleoside to a dNMP is the rate-limiting step of nucleotide synthesis and, in many cases, MDS patients lack the enzyme responsible for this transformation. Such considerations require high doses of nucleosides, dNMPs, dNDPs or dNTPs to potentially achieve therapeutic benefit.
Thus, there is a need for new therapies for MDS, and in particular for therapies that can effectively provide dNMPs, dNDPs or dNTPs to mitochondria.